U.S. patent application number 11/441278 was filed with the patent office on 2006-11-30 for pharmaceutical combinations.
Invention is credited to John Dixon, Robert Humphries, Gavin Jarvis, Ian Kirk.
Application Number | 20060270607 11/441278 |
Document ID | / |
Family ID | 20417947 |
Filed Date | 2006-11-30 |
United States Patent
Application |
20060270607 |
Kind Code |
A1 |
Dixon; John ; et
al. |
November 30, 2006 |
Pharmaceutical combinations
Abstract
The present invention provides novel pharmaceutical combinations
and their use in anti-thrombotic therapy.
Inventors: |
Dixon; John; (Loughborough,
GB) ; Humphries; Robert; (Loughborough, GB) ;
Jarvis; Gavin; (Oxford, GB) ; Kirk; Ian;
(Loughborough, GB) |
Correspondence
Address: |
WHITE & CASE LLP;PATENT DEPARTMENT
1155 AVENUE OF THE AMERICAS
NEW YORK
NY
10036
US
|
Family ID: |
20417947 |
Appl. No.: |
11/441278 |
Filed: |
May 25, 2006 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10148526 |
May 31, 2002 |
|
|
|
PCT/SE00/02378 |
Nov 29, 2000 |
|
|
|
11441278 |
May 25, 2006 |
|
|
|
Current U.S.
Class: |
514/1.3 ;
514/13.6; 514/13.9; 514/14.7; 514/14.9; 514/165; 514/301; 514/457;
514/47; 514/56 |
Current CPC
Class: |
A61K 2300/00 20130101;
A61K 2300/00 20130101; A61K 31/7076 20130101; A61P 7/02 20180101;
A61P 7/00 20180101; A61K 45/06 20130101; A61K 31/397 20130101; A61P
43/00 20180101; A61K 31/7076 20130101; A61K 31/397 20130101 |
Class at
Publication: |
514/018 ;
514/047; 514/165; 514/301; 514/056; 514/457 |
International
Class: |
A61K 38/05 20060101
A61K038/05; A61K 31/7076 20060101 A61K031/7076; A61K 31/727
20060101 A61K031/727; A61K 31/4743 20060101 A61K031/4743; A61K
31/60 20060101 A61K031/60 |
Foreign Application Data
Date |
Code |
Application Number |
Dec 1, 1999 |
SE |
9904377-0 |
Claims
1. A kit of parts comprising: (a) a P.sub.2T receptor antagonist or
a pharmaceutically acceptable derivative thereof (component a); and
(b) another anti-thrombotic agent or a pharmaceutically acceptable
derivative thereof (component b); where components (a) and (b) are
each provided in a form (which may be the same or different) that
is suitable for administration in conjunction with each other.
2. A kit of parts according to claim 1, wherein component (a) is a
compound of formula (I): ##STR2## wherein: either R.sub.1 is
3,3,3-trifluoropropyl and R.sub.2 is 2-(methylthio)ethyl or R.sub.1
is propyl and R.sub.2 is hydrogen, or a pharmaceutically acceptable
derivative thereof.
3. A kit of parts according to claim 1, wherein component (b) is
selected from the group consisting of an anti-platelet agent, an
anti-coagulant agent, a fibrinolytic agent, and any combination
thereof.
4. A kit of parts according to any one of claim 1, wherein
component (b) is selected from the group consisting of aspirin,
clopidogrel, ticlopidine, a GPIIb/IIIa antagonist, a direct
thrombin inhibitor, a prodrug of a direct thrombin inhibitor,
warfarin, heparin, a low molecular weight heparin, tissue
plasminogen activator, tenecteplase, and any combination
thereof.
5. A kit of parts according to claim 1, wherein component (b) is a
direct thrombin inhibitor and/or a prodrug of a direct thrombin
inhibitor.
6. A kit of parts as claimed in claim 5, wherein the thrombin
inhibitor is melagatran.
7. A kit of parts as claimed in claim 5, wherein the prodrug of
melagatran is EtO.sub.2C--CH.sub.2--(R)Cgl-Aze-Pab-OH.
8. A kit of parts according to claim 7, wherein components (a) and
(b) are suitable for sequential, separate and/or simultaneous
administration.
9. (canceled)
10. (canceled)
11. A method of treating thrombosis which comprises using a kit of
parts according to claim 1, for administering a therapeutically
effective amount of a P.sub.2T receptor and another anti-thrombotic
agent to a person suffering from or susceptible to such a
disorder.
12. A method according to claim 11, wherein component (a) is
administered parenterally prior to surgery and component (b) is
administered orally following that surgery.
13. (canceled)
14. A pharmaceutical formulation comprising (a) a P.sub.2T receptor
antagonist or a pharmaceutically acceptable derivative thereof; and
(b) another anti-thrombotic agent or a pharmaceutically acceptable
derivative thereof; in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
15. A pharmaceutical formulation according to claim 14, wherein the
P.sub.2T receptor antagonist is a compound of formula (I) ##STR3##
wherein: either R.sub.1 is 3,3,3-trifluoropropyl and R.sub.2 is
2-(methylthio)ethyl or R.sub.1 is propyl and R.sub.2 is hydrogen,
or a pharmaceutically acceptable derivative thereof.
16. A pharmaceutical formulation according to claim 14, wherein
component (b) is selected from the group consisting of an
anti-platelet agent, an anti-coagulant agent, a fibrinolytic agent,
and any combination thereof.
17. A pharmaceutical formulation according to claim 14, wherein
component (b) is selected from the group consisting of aspirin,
clopidogrel, ticlopidine, a GPIIb/IIIa antagonist, a direct
thrombin inhibitor, a prodrug of a direct thrombin inhibitor,
warfarin, heparin, a low molecular weight heparin, tissue
plasminogen activator, tenecteplase, and any combination
thereof.
18. A pharmaceutical formulation according to claim 14, wherein
component (b) is a direct thrombin inhibitor and/or a prodrug of a
direct thrombin inhibitor.
19. A pharmaceutical formulation according to claim 18, wherein the
thrombin inhibitor is melagatran.
20. A pharmaceutical formulation according to claim 18, wherein the
prodrug of melagatran is
EtO.sub.3C--CH.sub.3--(R)Cgl-Aze-Pab-OH.
21. (canceled)
22. (canceled)
23. (canceled)
24. A method of treating thrombosis which comprises administering a
therapeutically effective amount of a pharmaceutical formulation
according to claim 14 to a person suffering from or susceptible to
such a disorder.
25. A process for the preparation of a pharmaceutical formulation
according to claim 14 which comprises mixing a P.sub.2T receptor
antagonist with another anti-thrombotic agent.
26. (canceled)
27. (canceled)
28. (canceled)
29. A method of treating thrombosis which comprises administering
to a person suffering from, or susceptible to such a condition; (a)
a pharmaceutical formulation comprising a P.sub.2T receptor
antagonist, or a pharmaceutically acceptable derivative thereof, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier, and (b) a pharmaceutical formulation comprising another
anti-thrombotic agent or a pharmaceutically acceptable derivative
thereof, in admixture with a pharmaceutically acceptable adjuvant,
diluent or carrier.
30. A method according to claim 29, wherein the P.sub.2T receptor
antagonist is a compound of formula (I) ##STR4## wherein: either
R.sub.1 is 3,3,3-trifluoropropyl and R.sub.2 is 2-(methylthio)ethyl
or R.sub.1 is propyl and R.sub.2 is hydrogen, or a pharmaceutically
acceptable derivative thereof.
31. A method according to claim 29, wherein component (b) is
selected from the group consisting of an anti-platelet agent, an
anti coagulant agent, and any combination thereof.
32. A method according to claim 29, wherein component (b) is
selected from the group consisting of aspirin, clopidogrel,
ticlopidine, a GPIIb/IIIa antagonist, a direct thrombin inhibitor,
a prodrug of a direct thrombin inhibitor, warfarin, heparin, a low
molecular weight heparin, tissue plasminogen activator,
tenecteplase, and any combination thereof.
33. A method according to claim 29, wherein component (b) is a
direct thrombin inhibitor and/or a prodrug of a direct thrombin
inhibitor.
34. A method according to claim 33, wherein the thrombin inhibitor
is melagatran.
35. A method according to claim 33, wherein the prodrug of
melagatran is EtO.sub.2C--CH.sub.2--(R)Cgl-Aze-Pab-OH.
36. A method according to claim 29, wherein component (a) is a
parenteral formulation and component (b) is an oral
formulation.
37. A method according to claim 36, wherein component (a) is
administered parenterally prior to surgery and component (b) is
administered orally following that surgery.
38. (canceled)
39. (canceled)
Description
FIELD OF THE INVENTION
[0001] The present invention relates to pharmaceutical combinations
comprising a P.sub.2T receptor antagonist and another
anti-thrombotic agent and to their use in the treatment and
prevention of thrombosis.
BACKGROUND OF THE INVENTION
[0002] Increased understanding of the mechanisms underlying
thrombosis and of interventions therein has led to a
polypharmacological anti-thrombotic approach utilising appropriate
combinations of anti-platelet, anti-coagulant and fibrinolytic
agents. Examples of anti-thrombotic compounds used include
anti-platelet agents such as aspirin, clopidogrel, ticlopidine,
GPIIb/IIIa antagonists; anti-coagulants such as thrombin
inhibitors, warfarin, heparin and low molecular weight heparins;
and fibrinolytic agents including but not limited to,
streptokinase, tissue plasminogen activator (tPA) and
tenecteplase.
[0003] Most patients with acute myocardial infarction are currently
treated using either a thrombolytic agent or intervention treatment
with percutaneous coronary angioplasty (PTCA). It has been shown
that the use of both these methods result in an increase in the
number of patients achieving acceptable coronary artery patency at
90 minutes, and that the better the flow in the affected coronary
artery, the greater the survival.
[0004] However, even the most effective thrombolytic agents with
adjunctive aspirin and heparin treatment are only moderately
effective in achieving coronary artery patency with normal blood
flow (assessed as TIMI grade 3) in about 50% of cases. In addition,
in the acute setting where immediate effect is paramount,
slow-acting agents leave a window where the patient is not
protected from thrombosis. For example, clopidogrel inhibits
ADP-induced platelet aggregation and, like the earlier analogue,
ticlopidine, has shown clinical efficacy in arterial thrombosis.
However, both agents produce incomplete, slow to develop inhibition
of the ADP response, properties which are far from ideal in acute
therapy, such as prevention of stent occlusion, although increasing
use of a loading dose has been a recent advance.
[0005] Another short-coming of existing anti-thrombotic agents, and
combinations thereof, is that the optimal pharmacodynamic
risk:benefit (anti-thrombotic:anti-haemostatic) relationship has
not yet been achieved.
[0006] Thus there is a need for more effective anti-thrombotic
therapy.
[0007] Recently it has been shown that P.sub.2T (also known as
P2Y.sub.ADP or P2T.sub.AC) receptor antagonists offer significant
improvements over other anti-thrombotic agents. The P.sub.2T
receptor is primarily involved in mediating platelet
aggregation/activation and is a G-protein coupled receptor. The
pharmacological characteristics of this receptor have been
described, for example, in the references by Humphries et al., Br.
J. Pharmacology (1994), 113, 1057-1063, and Fagura et al., Br. J.
Pharmacology (1998) 124, 157-164.
[0008] International Patent Applications WO 92/17488 and WO
94/18216 disclose novel P.sub.2T receptor antagonists and thereof,
including compounds of formula (I) (see below). Compound A (a
compound of formula (I) wherein R.sub.1 is 3,3,3-trifluoropropyl
and R.sub.2 is 2-(methylthio)ethyl) is disclosed in WO 94/18216.
Compound B (a compound of formula (I) wherein R.sub.1 is propyl and
R.sub.2 is hydrogen) is disclosed in WO 92/17488.
[0009] Both compound A and compound B may be used in any condition
where platelet activation or aggregation is involved. The compounds
may thus act as anti-thrombotic agents and are useful in the
treatment or prophylaxis of unstable angina, thromboembolic stroke
and peripheral vascular disease. They may also be used in the
treatment and prophylaxis of the sequalae of thrombotic
complications from angioplasty, thrombolysis, endarterectomy,
coronary and vascular graft surgery, renal dialysis and
cardiopulmonary bypass. In addition, they can be used in the
treatment and prophylaxis of disseminated intravascular
coagulation, deep vein thrombosis, pre-eclampsia, tissue salvage
following surgical or accidental trauma, vasculitis, arteritis,
thrombocythaemia, ischemia and migraine.
DISCLOSURE OF THE INVENTION
[0010] The inventors of the present invention have surprisingly
found that administration of a combination of a P.sub.2T receptor
antagonist or a pharmaceutically acceptable derivative thereof, and
another anti-thrombotic agent or a pharmaceutically acceptable
derivative thereof, offers a significant improvement over other
anti-thrombotic treatments.
[0011] Accordingly, the combined administration of a P.sub.2T
receptor antagonist or a pharmaceutically acceptable derivative
thereof and another anti-thrombotic agent or a pharmaceutically
acceptable derivative thereof, can be used in the treatment and
prevention of thrombosis, particularly in the treatment of the
thrombotic complications of atherosclerotic disease and
interventions therein.
[0012] According to a first aspect of the invention there is
provided a kit of parts comprising:
(a) a P.sub.2T receptor antagonist or a pharmaceutically acceptable
derivative thereof (component a); and
(b) another anti-thrombotic agent or a pharmaceutically acceptable
derivative thereof (component b);
where components (a) and (b) are each provided in a form (which may
be the same or different) that is suitable for administration in
conjunction with each other.
[0013] Pharmaceutically acceptable derivatives of a P.sub.2T
receptor antagonist and other anti-thrombotic agent include salts
(e.g. pharmaceutically acceptable non-toxic organic or inorganic
acid addition salts (such as a salt of hydrochloric, hydrobromic,
nitric, sulphuric or acetic acid)), solvates and solvates of
salts.
[0014] If more than one formulation comprising component (a) or
component (b) is present, for example in order to provide for
repeat dosing, such formulations may be the same, or may be
different in terms of the dosage, chemical composition and/or
physical form.
[0015] Preferably, the P.sub.2T receptor antagonist is the compound
of formula (I): ##STR1## wherein: either R.sub.1 is
3,3,3-trifluoropropyl and R.sub.2 is 2-(methylthio)ethyl or R.sub.1
is propyl and R.sub.2 is hydrogen; or a pharmaceutically acceptable
derivative thereof.
[0016] More preferably, the P.sub.2T receptor antagonist is
compound A (where R.sub.1 is 3,3,3-trifluoropropyl and R.sub.2 is
2-(methylthio)ethyl as disclosed in WO 94/18216).
[0017] Preferably component (b) is selected from anti-platelet
agents, anti-coagulant agents, fibrinolytic agents, and any
combination thereof.
[0018] More preferably, component (b) is selected from the group
consisting of aspirin, clopidogrel, ticlopidine, a GPIIb/IIIa
antagonist, direct thrombin inhibitors, prodrugs of direct thrombin
inhibitors, warfarin, heparin, low molecular weight heparins,
streptokinase, tissue plasminogen activator, tenecteplase and any
combination thereof. Examples of direct thrombin inhibitors include
melagatran (WO 94/29336). Prodrugs of melagatran include those
described in WO 97/23499, and particularly include Example 17 of
that application. Example 17 of WO 97/23499 is H 376, which is
EtO.sub.2C--CH.sub.2--(R)Cgl-Aze-Pab-OH, wherein Cgl is
cyclohexylglycinyl, Aze is (S)-azetidine-2-carbonyl and Pab is
para-amidinobenzylamino and the OH replaces one of the amidino
hydrogens in Pab.
[0019] In accordance with the invention, the P.sub.2T receptor
antagonist, other anti-thrombotic agent, and derivatives of either,
may be administered orally, intravenously, subcutaneously,
buccally, rectally, dermally, nasally, tracheally, bronchially,
topically, or via inhalation into the lung. Preferred modes of
delivery are systemic. For the P.sub.2T receptor antagonist and
derivatives thereof, preferred modes of administration are
parenteral, more preferably intravenous. For the other
anti-thrombotic agent and derivatives thereof, preferred modes of
administration are oral or, in the case of unfractionated or low
molecular weight heparins, certain direct thrombin inhibitors and
fibrinolytic agents, intravenous or subcutaneous.
[0020] The sequence in which the formulations comprising the
P.sub.2T receptor antagonist and the other anti-thrombotic agent
may be administered (i.e. whether, and at what point, sequential,
separate and/or simultaneous administration takes place) may be
determined by the physician or skilled person. For example, the
sequence may depend upon many factors, such as whether, at any time
during the course or period of treatment, one or other of the
formulations cannot be administered to the person for practical
reasons (e.g. the person is unconscious and thus unable to take an
oral formulation).
[0021] Respective formulations comprising component (a) and/or
component (b) may be administered, sequentially, separately and/or
simultaneously, over the course of treating the relevant condition,
which condition may be acute or chronic. Preferably, the two
formulations are administered (optionally repeatedly) sufficiently
closely in time for there to be a beneficial effect for the
patient, that is greater, over the course of the treating the
relevant condition, than if either of the two formulations are
administered (optionally repeatedly) alone, in the absence of the
other formulation, over the same course of treatment. Determination
of whether a combination provides a greater beneficial effect in
respect of, and over the course of treatment of a particular
condition, will depend upon the condition to be treated or
prevented, but may be achieved routinely by the skilled person.
[0022] Alternatively, one or other of the two component
formulations may be administered (optionally repeatedly) prior to,
after, and/or at the same time as, administration with the other
component. Individual doses of a P.sub.2T receptor antagonist and
other anti-thrombotic agent may be used within 48 hours (e.g. 24
hours) of each other.
[0023] In the therapeutic treatment of mammals, and especially
humans, the P.sub.2T receptor antagonist, other anti-thrombotic
agent, and derivatives of either, may be administered alone, but
will generally be administered as a pharmaceutical formulation in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier, which should be selected with due regard to the intended
route of administration and standard pharmaceutical practice.
[0024] In accordance with the invention, the kit of parts may be
used in medical therapy, suitably in the treatment of thrombosis.
The treatment of thrombosis will be understood by those skilled in
the art to include the treatment and prevention of thrombotic
complications of atherosclerotic disease and interventions therein,
such as fibrinolysis, endarterectomy or percutaneous transluminal
coronary revascularisation (PTCR), including, but not limited to,
percutaneous transluminal coronary angioplasty (PTCA) with or
without stenting. Thrombotic complications of atherosclerotic
disease include, but are not limited to, acute coronary syndrome
(encompassing acute myocardial infarction with or without ST
elevation and unstable angina) and thrombotic stroke.
[0025] A further aspect of the invention provides a method of
treating thrombosis (for example thrombotic complications of
atherosclerotic disease and interventions therein, such as
fibrinolysis, endarterectomy or percutaneous transluminal coronary
revascularisation (PTCR), including, but not limited to,
percutaneous transluminal coronary angioplasty (PTCA) with or
without stenting) which comprises using a kit of parts for
administering a therapeutically effective amount of a P.sub.2T
receptor and another anti-thrombotic agent to a person suffering
from or susceptible to such a disorder.
[0026] For avoidance of doubt the term "treatment" includes
therapeutic and/or prophylactic treatment.
[0027] Preferably component component (a) is administered
parenterally prior to surgery and component (b) is administered
orally following that surgery.
[0028] According to another aspect of the invention, there is
provided a method of making a kit of parts as defined herein, which
comprises bringing a component (a) into association with a
component (b) thus rendering the two components suitable for
administration in conjunction with each other. By bringing the two
components into association with each other, we include that
components (a) and (b) may be:
i) packaged presented and purchased as separate formulations which
are subsequently used in conjunction in combination therapy; or
ii) packaged and presented together as separate components of a
combination pack for use in conjunction with each other in
combination therapy.
[0029] The present invention still further provides a kit of parts
comprising:
(1) components (a) and (b) as defined herein; together with
(2) instructions to use the components in conjunction with each
other.
[0030] The invention further provides the use of a P.sub.2T
receptor antagonist, or a pharmaceutically acceptable derivative
thereof, in the manufacture of a kit of parts for the treatment of
thrombosis.
[0031] Components (a) and (b) as described herein may also be
co-formulated as a combined preparation (i.e. presented as a single
formulation including a P.sub.2T receptor antagonist and other
anti-thrombotic agent).
[0032] Thus, a further aspect of the invention provides a
pharmaceutical formulation comprising:
(a) a P.sub.2T receptor antagonist or a pharmaceutically acceptable
derivative thereof; and
(b) another anti-thrombotic agent or a pharmaceutically acceptable
derivative thereof; in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier.
[0033] Preferably component (a) is a compound of formula (I) as
defined above, or a pharmaceutically acceptable derivative thereof.
Preferably component (b) is selected from anti-platelet agents,
anti-coagulant agents, fibrinolytic agents, and any combination
thereof. More preferably, component (b) is selected from the group
consisting of aspirin, clopidogrel, ticlopidine, a GPIIb/IIIa
antagonist, direct thrombin inhibitors, prodrugs of direct thrombin
inhibitors, warfarin, heparin, low molecular weight heparins,
tissue plasminogen activator, tenecteplase, and any combination
thereof.
[0034] The present invention provides a pharmaceutical formulation
comprising:
(a) a P.sub.2T receptor antagonist or a pharmaceutically acceptable
derivative thereof; and
(b) another anti-thrombotic agent or a pharmaceutically acceptable
derivative thereof; in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier;
for use in medical therapy, suitably in the treatment of
thrombosis.
[0035] The invention further provides a method of treating
thrombosis which comprises administering a therapeutically
effective amount of a pharmaceutical formulation comprising:
(a) a P.sub.2T receptor antagonist or a pharmaceutically acceptable
derivative thereof; and
(b) another anti-thrombotic agent or a pharmaceutically acceptable
derivative thereof; in admixture with a pharmaceutically acceptable
adjuvant, diluent or carrier;
to a person suffering from or susceptible to such a disorder.
[0036] In another aspect of the present invention, there is
provided a process for the preparation of a pharmaceutical
formulation which comprises mixing a P.sub.2T receptor antagonist
with another anti-thrombotic agent.
[0037] The invention further provides the use of a pharmaceutical
formulation as hereinbefore defined in the manufacture of a
medicament for the treatment of thrombosis.
[0038] Another aspect of the invention involves the use of:
(a) a pharmaceutical formulation comprising a P.sub.2T receptor
antagonist or a pharmaceutically acceptable derivative thereof, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier; and
(b) a pharmaceutical formulation comprising another anti-thrombotic
agent or a pharmaceutically acceptable derivative thereof, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier,
in therapy, suitably in the treatment of thrombosis.
[0039] A further aspect of the invention provides a method of
treating thrombosis which comprises administering:
a) a pharmaceutical formulation comprising a P.sub.2T receptor
antagonist or a pharmaceutically acceptable derivative thereof, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier, and
b) a pharmaceutical formulation comprising another anti-thrombotic
agent or a pharmaceutically acceptable derivative thereof, in
admixture with a pharmaceutically acceptable adjuvant, diluent or
carrier,
to a person suffering from or susceptible to such a disorder.
[0040] In another aspect of the present invention, there is
provided the use of a P.sub.2T receptor antagonist, or a
pharmaceutically acceptable derivative thereof, in the manufacture
of a medicament to be used in combination with another
anti-thrombotic agent in the treatment of thrombosis. Preferably
the P.sub.2T receptor antagonist is a compound of formula (I), or a
pharmaceutically acceptable derivative thereof.
[0041] Suitable formulations for administering a P.sub.2T receptor
antagonist are known in the art, and include those known from WO
92/17488 and WO 94/18216.
[0042] Suitable formulations for administering other
anti-thrombotic agent are described in the literature, for example,
when the other anti-thrombotic agent is melagatran, or a prodrug of
melagatran, suitable formulations include those described in inter
alia WO 94/29336, WO 96/14084, WO 96/16671, WO 97/23499, WO
97/39770, WO 97/45138, WO 98/16252, WO 99/27912, WO 99/27913, WO
00/13672 and WO 00/12043. Otherwise, the preparation of suitable
formulations may be achieved by the skilled person using routine
techniques.
[0043] Suitable doses of the P.sub.2T receptor antagonist, the
other anti-thrombotic agent, and derivatives of either can be
determined by the medical practitioner or other skilled person, and
will depend on the severity of the condition, and on the person to
be treated, as well as the compound(s) which is/are employed.
Respective doses are discussed in the prior art documents
disclosing P.sub.2T receptor antagonists and other anti-thrombotic
agents that are mentioned hereinbefore.
[0044] In the case of a compound of formula (I), suitable doses of
active compound in the therapeutic and/or prophylactic treatment of
mammalian, especially human, patients include those which give a
mean plasma concentration of up to 5 .mu.mol/L, for example in the
range 0.001 to 5 .mu.mol/L over the course of treatment of the
relevant condition. In any event, the physician, or the skilled
person, will be able to determine the actual dosage which will be
most suitable for an individual person, which is likely to vary
with the condition that is to be treated, as well as the age,
weight, sex and response of the particular person to be treated.
The above-mentioned dosages are exemplary of the average case.
There can, of course, be individual instances where higher or lower
dosage ranges are merited, and such are within the scope of this
invention.
[0045] The pharmaceutical formulation of the invention may, and
indeed will usually, contain various other ingredients known in the
art, for example preservatives, stabilising agents,
viscosity-regulating agents, emulsifying agents or buffering
agents. Thus the pharmaceutical formulation of the invention will
typically comprise a total amount of (a) the P.sub.2T receptor
antagonist and (b) another anti-thrombotic agent (the active
ingredients) in the range from 0.05 to 99% w (percent by weight),
more preferably in the range from 0.10 to 70% w, and even more
preferably in the range from 0.10 to 50% w, all percentages by
weight being based on total formulation.
EXAMPLES
[0046] The invention is illustrated, but in no way limited, by the
following examples, either utilising compound A (a compound of
formula (I) wherein R.sub.1 is 3,3,3-trifluoropropyl and R.sub.2 is
2-(methylthio)ethyl) or, in Example 3, using data obtained with the
close structural analogue, compound B (a compound of formula (I)
wherein R.sub.1 is propyl and R.sub.2 is hydrogen, synthesised at
AstraZeneca R & D, Charnwood, Humphries et al (1995), Br J
Pharmacol., 115; 1110-1116).
Example 1
Canine Coronary Thrombosis Model--Compound A and
Aspirin/Heparin
[0047] Compound A was used in combination with aspirin and
unfractionated heparin in a dog model of coronary artery thrombosis
to determine whether addition of a P.sub.2T-receptor antagonist to
these standard anti-platelet and anti-coagulant agents could
improve coronary artery patency after thrombolysis with tPA. All
animals were treated with both aspirin 325 mg and unfractionated
heparin 80 U/kg then 17 U/kg/h. The test group (n=10) was treated
with compound A (4 .mu.g/kg/min iv) from 10 min prior to tPA until
end of protocol (2 h post reperfusion). The placebo group (n=10)
received only a saline infusion iv from 10 min prior to tPA until
end of protocol (2 h post reperfusion).
[0048] The results of the experiments are evident in tables 1 and
2.
[0049] Coronary artery blood flow following successful thrombolysis
with tPA was significantly better maintained in a group of animals
receiving compound A in addition to aspirin and heparin than in a
group receiving saline, aspirin and heparin (table 1).
TABLE-US-00001 TABLE 1 Effects on coronary thrombolysis by tPA
Parameter Saline Compound A Baseline blood flow (ml/min) 65.3 .+-.
7.5 62.3 .+-. 8.5 ns Time to occlusion (min) 55.5 .+-. 14.0 62.3
.+-. 14.7 ns Reperfusion rate 100% 100% ns Time to reflow (min)
21.5 .+-. 2.9 20 .+-. 6.1 ns Reflow duration (min) 75.0 .+-. 39.9
119.7 .+-. 0.7* Cyclic flow variation 50% 0%* Reocclusion 60% 0%*
*P < 0.05
[0050] Infarct size was also reduced significantly (P<0.05) in
animals receiving compound A (table 2). These results suggest that
significant additional clinical benefit will be attained when a
P.sub.2T antagonist is combined with a fibrinolytic agent and
standard anti-platelet and anti-coagulant therapy. TABLE-US-00002
TABLE 2 Infarct size reduction Saline Compound A Area at risk
(cm.sup.2) 48.7 .+-. 6.9 49.9 .+-. 8.4 Ns Infarct size (cm.sup.2)
9.3 .+-. 4.4 4.7 .+-. 4.7 P = 0.034
Example 2
Human Blood In Vitro--Compound A and Clopidogrel
[0051] Compound A (500 nM final concentration) was added to blood
from healthy human volunteers receiving clopidogrel
(Sanofi-Winthrop, 75 mg/day for 11 days). ADP-induced platelet
aggregation (+/-compound A) was measured using whole blood
impedance aggregometry.
[0052] Clopidogrel alone resulted in slowly developing, incomplete
inhibition of the ADP response (Table 3). Compound A added in vitro
produced complete or near complete inhibition of the response to
low to intermediate concentrations of ADP (up to 30 .mu.M) both
before and during administration of clopidogrel (data for ADP 10
.mu.M shown in Table 3) while substantial inhibition of the
response to the highest concentration of ADP used (300 .mu.M)
required a combination of both compound A and clopidogrel.
TABLE-US-00003 TABLE 3 Effect of oral clopidogrel (75 mg/day) on
ADP (10 and 300 .mu.M)-induced platelet aggregation measured in
blood from healthy human volunteers ex vivo (+/-compound A (500 nM)
added in vitro) Aggregation (ohms) Duration of (mean .+-. SD, n =
7-8 except where indicated) clopidogrel ADP 10 .mu.M ADP 300 .mu.M
administra- -compound +compound -compound +compound tion (days) A A
A A 0 14.9 .+-. 1.9 0.5 .+-. 0.7 Not measured 6.5 .+-. 3.4 1 13.8
.+-. 2.3 0.4 .+-. 0.7 Not measured 4.2 .+-. 2.6 2 11.8 .+-. 3.4 0.4
.+-. 0.6 Not measured 2.9 .+-. 2.3 3 10.2 .+-. 4.5 0.6 .+-. 0.7
13.9.sup.(n=1) 2.7 .+-. 2.1 11 8.2 .+-. 4.4 0.6 .+-. 0.8 11.4 .+-.
5.2.sup.(n=3) 2.8 .+-. 2.8
Example 3
[0053] P-selectin expression on the platelet membrane surface plays
an important role in platelet-leukocyte-conjugate formation and
there is increasing evidence that such interactions play an
important role in both acute thrombosis and in the inflammatory
aetiology of progressive atheroscerosis. The effect of a
P.sub.2T-receptor antagonist (compound B) on ADP (10 .mu.M)-induced
platelet P-selectin expression was investigated in human washed
platelets. The effect of compound B (10 nM) was compared with that
of the GPIIb/IIIa antagonist, GR144053 (10 .mu.M, Foster et al
(1993) Thromb Haemostas; 69(6):559, synthesized in AstraZeneca R
& D, Charnwood). These concentrations are 4 (compound B)--and
600 (GR144053)--fold higher than the respective IC.sub.50 values
for inhibition of ADP-induced platelet aggregation in this system.
The results are summarised in Table 4. TABLE-US-00004 TABLE 4
Effect of compound B and GR144053 alone or in combination on ADP
(10 .mu.M)-induced P-selectin expression in human washed platelets
P-selectin expression (% positive cells) Conditions Mean .+-. se (n
= 3) Control 13.1 .+-. 3.3 +GR144053 (10 .mu.M) 17.7 .+-. 1.7
+compound B (10 nM) 4.9 .+-. 2.6 +GR144053 (10 .mu.M) + 7.5 .+-.
1.6 compound B (10 nM)
[0054] The P.sub.2T-receptor antagonist, at a concentration
consistent with known effects on ADP-induced platelet aggregation,
substantially inhibits ADP-induced P-selectin expression in the
absence or presence of the GPIIb/IIIa antagonist. In contrast, the
GPIIb/III antagonist alone had no effect on P-selectin expression
at a concentration considerably in excess of that which would
completely inhibit platelet aggregation. These results suggest the
potential for combination therapy with GPIIb/IIIa antagonists and
P.sub.2T-receptor antagonists, wherein the broad-spectrum
anti-aggregatory effect of the former class is complemented by the
additional effect of the latter on other aspects of platelet
activation, such as pro-inflammatory P-selectin expression.
Abbreviations
ADP=adenosine diphosphate
GPIIb/IIIa antagonist=glycoprotein IIb/IIIa antagonist
PTCR=percutaneous transluminal coronary revascularisation
PTCA=percutaneous transluminal coronary angioplasty
TIMI=thrombolysis in myocardial infarction
tPA=tissue plasminogen activator
* * * * *